Pancreatic ductal adenocarcinoma (PDA) has an exceedingly poor prognosis with a 5-year survival of only ~6%. Unlike many other cancers, current strategies do NOT target genetic features of PDA. In part, this is because PDA is viewed as a disease that is dominated by KRAS as the oncogenic driver. As a result, therapies delivered to PDA are not targeted based on biomarkers, and chemotherapy is the mainstay for treatment. To define new means to treat PDA, we performed genetic analysis of >100 PDA cases by exome sequencing. These data revealed aberrations in multiple pathways. In particular, alterations in chromosome stability processes or cell cycle control were observed in >75% of cases. These pathways are inter-related, and would be expected to remain actionable in spite of the common deregulated KRAS signaling in PDA. Genetic alterations can lead to tumor-specific vulnerabilities that can be exploited for treatment. Here we will approach rational targeting of genetic events in PDA using two complementary efforts. First, we have defined loss/mutation of multiple pathways associated with chromosome-fidelity. These events individually are rare, but when coalesced into pathways/functional groups represent >30% of PDA patents. Our group and others have found that a specific subset of genetic events represent vulnerabilities that can be selectively targeted. Most notably germline BRCA/PALB2 mutations are the basis of the only active Phase III trial for patients with PDA. However, whether other pathways associated with chromosomal instability can be effectively targeted is unknown. These findings provide the impetus for a detailed analysis of the confluence of loss of genes involved in genome stability, resultant biological output in PDA, and selective therapeutic sensitivities. Second, therapeutic strategies can re-instate tumor suppressor activities that have been disrupted in PDA and limit proliferation to control disease. Loss of cell cycle regulatory control over CDK4/6 occurs frequently in >50% of PDA cases through loss of p16ink4a. Therefore, CDK4/6 inhibition would be expected to be exceedingly effective in PDA treatment. However, the response to CDK4/6 inhibitors is variable and cell cycle regulatory networks in PDA are particularly complex suggesting that other genetic events impinge on the efficacy of CDK4/6 inhibition. These findings provide the basis for defining the determinants of durable response to CDK4/6 inhibitors, delineating successful combination therapies, and defining the utility of such agents in disease relevant models of PDA. In total, these studies interrogate the hypothesis that therapeutic approaches targeting genetic features of PDA controlling genome stability and cell cycle control will provide critical advances to treatment.